The long-term objective of this application is to study the effect of interactions between aging and alcoholism on the immune system. Both alcoholism and aging are associated with an increased risk for immune- related disorders such as infection and cancer. Both alcoholism and aging are also associated with dysregulation of immune function. We initially hypothesized that the combined effects of alcoholism and aging will result in a further decline in immune function. Data gathered by our group and others indicate that age is an important factor in alcohol- induced immune dysregulation. The role that various cytokines play in such immune changes remain poorly understood. We now hypothesize that one mechanism of impaired immune function in both alcoholism and aging involves dysregulation of cytokine production, and that the combined effect of alcoholism and aging is a further decline in cytokine production and cytokine gene expression by different immune cells. To test these hypotheses, we will conduct both in-vitro and in-vivo studies to assess the production and gene expression of five key cytokines: interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL- 6), tumor necrosis factor (TNF) and interferon (INF). In the in-vitro studies, different concentrations of alcohol will be added in-vitro to cultures of whole blood/monocytes/lymphocytes of normal human donors of different age groups ranging between the newborn (cord blood) and the elderly (over 60 years old). Cytokine production and cytokine gene expression will be measured and interactions between alcohol concentrations and age groups will be assessed. In the in-vivo studies, cytokine production and cytokine gene expression of whole blood/monocyte/lymphocytes of alcoholic patients of different age groups and age-and-sex-matched normal controls will be compared and the relative contribution of aging and alcoholism to any differences in cytokine production or cytokine gene expression between the two groups will be analyzed. These proposed experiments constitute a logical continuation of our ongoing studies and may enhance our understanding about possible mechanisms of immunosuppression in elderly alcoholics. Knowledge about the role of cytokines in alcohol-induced immunosuppression in the elderly can potentially lead to intervention strategies that could decrease the risk of immune-related disorders in these individuals.